Physiologic increments of the counterregulatory hormones, glucagon, epinephrine and cortisol interact synergistically in the normal dog so as to produce marked fasting hyperglycemia. The synergistic nature of the hormonal interactions suggests that stress hyperglycemia cannot be ascribed to a single hormone, but results from the combined elevations of several hormones. In studies designed to evaluate the role of blood glucose per se in the regulation of hepatic glucose production in vivo, we demonstrated that: 1) elevations in glucose production in response in hypoglycemia occur independent of changes in circulating counterregulatory hormones; 2) hyperglycemia inhibits glucose production independent of a rise in insulin or a fall in glucagon; and 3) blood glucose modulates in the anti-insulin action of glucagon and epinephrine. Studies in the area of protein metabolism have demonstrated that exogenous leucine infusion results in hypoaminoacidemia and improvement in nitrogen balance in fasted humans and that carbohydrate restriction has an adverse effect on protein tolerance. Other data indicate that: 1) somatostatin accentuates hyperglycemia in maturity-onset diabetes and inhibits protein absorption and intestinal fluid secretion; 2) the hyperglycemic effects of glucagon in diabetes are reduced by intermittent hormone infusion; and 3) a pre-programmed portable pump which delivers insulin via the subcutaneous route is effective in normalizing blood glucose levels in "brittle" juvenile-onset diabetics.